The invention relates to cyclic nonapeptide amides and methods for their preparation as well as to their use for the production of medicaments for the treatment and/or prophylaxis of diseases, especially bacterial infectious diseases.
The bacterial cell wall is synthesized by a number of enzymes (cell wall biosynthesis) and is essential for the survival and reproduction of microorganisms. The structure of this macromolecule, as well as the proteins involved in its synthesis, are highly conserved within the bacteria. Owing to its essential nature and uniformity, cell wall biosynthesis is an ideal point of attack for new antibiotics (D. W. Green, The bacterial cell wall as a source of antibacterial targets, Expert Opin. Ther. Targets (2002) 6:1-19).
Vancomycin and penicillins are inhibitors of bacterial cell wall biosynthesis and represent successful examples of the antibiotic potency of this principle of action. They have been employed for several decades clinically for the treatment of bacterial infections, in particular with Gram-positive pathogens. Owing to the growing occurrence of resistant microorganisms, for example methicillin-resistant Staphylococci, penicillin-resistant pneumococci and vancomycin-resistant enterococci (F. Baquero, Gram-positive resistance: challenge for the development of new antibiotics, J. Antimicrob. Chemother. (1997) (39), Suppl A:1-6; A. P. Johnson, D. M. Livermore, G. S. Tillotson, Antimicrobial susceptibility of Gram-positive bacteria: what's current, what's anticipated?, J. Hosp. Infect. (2001) (49), Suppl A:3-11), and also recently, for the first time, vancomycin-resistant Staphylococci (B. Goldrick, First reported case of VRSA in the United States, Am. J. Nurs. (2002) 102:17), these substances are increasingly losing their therapeutic efficacy.
The present invention describes a novel class of cell wall biosynthesis inhibitors without cross-resistances to known classes of antibiotics.
The natural product lysobactin and some derivatives are described as having antibacterial activity in U.S. Pat. No. 4,754,018. The isolation and antibacterial activity of lysobactin is also described in EP-A-196 042 and JP 01132600. WO04/099239 describes derivatives of lysobactin having antibacterial activity.
The antibacterial activity of lysobactin and katanosin A is furthermore described in O'Sullivan, J. et al., J. Antibiot. (1988) 41: 1740-1744, Bonner, D. P. et al., J. Antibiot. (1988) 41:1745-1751, Shoji, J. et al., J. Antibiot. (1988) 41:713-718 and Tymiak, A. A. et al., J. Org. Chem. (1989) 54:1149-1157.
The stability of an active compound is an important parameter for its suitability as a medicament. Among other factors, the stability plays a role in the storage and the administration of medicaments. Many natural products exhibit a stability insufficient for medicaments.
The antibacterially active depsipeptide lysobactin hydrolyzes in an aqueous neutral to basic medium (pH>7) within days. This forms the antibacterially inactive “open-lysobactin” which has been opened at the lactone. Active analogs of lysobactin with a higher ring stability are therefore desirable.